This program proposes to identify causes of pulmonary edema due primarily to changes in the lung circulation, to clarify biochemical and physical sequences of events involved in the pathogenesis of these changes and to develop quantitative methods for measuring lung vascular permeability in humans. In a chronic unanesthetized sheep preparation where lung lymph can be collected and hemodynamic variables measured, we will measure the effects of humoral mediators (prostaglandins, histamine, serotonin, adrenergic agents) on lung fluid balance. In the same preparation, we will clarify the pathogenesis of the pulmonary vascular response to endotoxemia by measuring lung prostaglandin release and by testing the effects of antagonists to humoral mediators, corticosteroids, heparin, prostaglandins and their inhibitors, adrenergic agents and xanthines on the endotoxin response. In humans we will make detailed pulmonary function and hemodynamic measurements in diseases where pulmonary edema occurs with heart failure, follow the course of these changes and evaluate indicator dilution techniques as a method for measuring lung vascular permeability. Using data from animal and human experiments, we will develop mathematical models of lung transvascular transport which will describe the physical events involved in this process under normal and abnormal conditions and will permit more accurate and precise estimates of lung vascular permeability in humans.